EP0233733A2 - Procédé de préparation de n-phthaloyl-p-nitro-1-phénylalanine - Google Patents

Procédé de préparation de n-phthaloyl-p-nitro-1-phénylalanine Download PDF

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Publication number
EP0233733A2
EP0233733A2 EP87301043A EP87301043A EP0233733A2 EP 0233733 A2 EP0233733 A2 EP 0233733A2 EP 87301043 A EP87301043 A EP 87301043A EP 87301043 A EP87301043 A EP 87301043A EP 0233733 A2 EP0233733 A2 EP 0233733A2
Authority
EP
European Patent Office
Prior art keywords
phenylalanine
nitro
phthaloyl
compound
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP87301043A
Other languages
German (de)
English (en)
Other versions
EP0233733A3 (fr
Inventor
Norifumi Sugita
Koichi Niimura
Masahiko Fujii
Takao Furusho
Chikao Yoshikumi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kureha Corp
Original Assignee
Kureha Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kureha Corp filed Critical Kureha Corp
Publication of EP0233733A2 publication Critical patent/EP0233733A2/fr
Publication of EP0233733A3 publication Critical patent/EP0233733A3/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

Definitions

  • melphalan which has been known as an excellent anti-tumor agent is p-bis(2-chloroethyl)-amino-L-phenylalanine, and to exhibit the anti-tumor effect, it is necessary that this compound is in the L-form, i.e., melphalan.
  • L-form i.e., melphalan.
  • D-form is called as medphalan and its racemic-(DL)-form is called as sarcolysine and although every one of these two substances is said to be an anticancer agent, its anticancer activity is far inferior to that of melphalan.
  • British Patent No. 1,377,336 discloses a process wherein sarcolysine (DL-form) is at first produced and melphalan (L-form) is isolated from sarcolysine.
  • DL-form sarcolysine
  • L-form melphalan
  • U.S. Patent No. 3,032,585 discloses a process wherein the intermediate compound, N-acetyl-p-nitro-DL- phenylalanine, is treated by brucine, etc. to separate thereof into the D-form and the L-form and melphalan is obtained from the thus separated L-form by conventional process.
  • the D-form and the L-form is separated to each other during the course of synthesizing melphalan, and in the point that the D-form which is low in necessity is synthesized to a certain extent, the process is not industrially profitable.
  • a process for synthesizing melphalan has also been described in F. BERGEL (J. Chem.
  • the largest defect of the process lies in the loss of the optical activity of compound III by the reaction of introducing a protective group into compound II.
  • the object of the present invention lies in the synthesis of N-phthaloyl-p-nitro-L-phenylalanine without losing the optical activity of p-nitro-L-phenylalanine and in a high efficiency.
  • the object of the present invention lies in the synthesis of N-phthaloyl-p-nitro-L-phenylalanine which is the intermediate raw material for producing melphalan which is an excellent anticancer agent.
  • the object of the present invention is to provide a process for synthesizing N-phthaloyl-p-nitro-L-phenylalanine from p-nitro-L-penylalanine while using an N-substituted phthalimide.
  • an organic- or inorganic solvent for instance, benzene, toluene, xylene, dioxane, methylene chloride, DMSO, DMF, DME, pyridine, water, formic acid, chloroform, acetone, THF, acetic acid, etc. may be used.
  • the above-mentioned reaction is carried out at a temperature of from -10 to 40° C, preferably from 0 to 20° C, and as a more preferable method, the reaction is carried out at a low temperature in the initial stage and then at a high temperature in the following stages. Namely, in the initial stage, the reaction is carried out at a temperature of from -10 to 10° C and then the reaction is continued at a temperature of from II to 40° C.
  • the total reaction time period is from 5 minutes to 24 hours, preferably from 10 minutes to 4 hours.
  • sodium carbonate, copper carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate and the like may be added.
  • the compound III is esterified to obtain compound IV.
  • the esterification may be carried out on compound II first and then bring into reaction with N-substituted phthalimide to get compound IV.
  • compound IV is reduced in the presence of palladium-calcium carbonate (Pd-CaCO 3 ), platinum oxide (Pt0 2 ), palladium-carbon (Pd-C) or Raney nickel to obtain amino compound V.
  • Pd-CaCO 3 palladium-calcium carbonate
  • Pt0 2 platinum oxide
  • Pd-C palladium-carbon
  • Raney nickel Raney nickel
  • reaction product was adjusted to pH of 2.5 by about 329 ml of 6N HCI aqueous solution, and the thus formed precipitate was collected by filtration and washed with water. After compressing and drying the thus washed precipitate, it was dissolved in about 2 litres of ethanol by heating to 60° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP87301043A 1986-02-19 1987-02-05 Procédé de préparation de n-phthaloyl-p-nitro-1-phénylalanine Ceased EP0233733A3 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP34474/86 1986-02-19
JP61034474A JPS62192357A (ja) 1986-02-19 1986-02-19 Ｎ−フタロイル−ｐ−ニトロ−Ｌ−フエニルアラニンの製造方法

Publications (2)

Publication Number Publication Date
EP0233733A2 true EP0233733A2 (fr) 1987-08-26
EP0233733A3 EP0233733A3 (fr) 1988-01-13

Family

ID=12415246

Family Applications (1)

Application Number Title Priority Date Filing Date
EP87301043A Ceased EP0233733A3 (fr) 1986-02-19 1987-02-05 Procédé de préparation de n-phthaloyl-p-nitro-1-phénylalanine

Country Status (4)

Country Link
EP (1) EP0233733A3 (fr)
JP (1) JPS62192357A (fr)
AU (1) AU575742B2 (fr)
PH (1) PH23371A (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0317281A2 (fr) * 1987-11-19 1989-05-24 The Wellcome Foundation Limited Formulations pharmaceutiques contenant du melphalan ou du chlorhydrate de melphalan, le melphalan et le chlorhydrate de melphalan et procédés pour les préparer
EP2268827A1 (fr) * 2008-03-20 2011-01-05 Navinta, llc. Procédé permettant de produire du melphalan optiquement pur
CN102030671A (zh) * 2010-10-26 2011-04-27 浙江凯普化工有限公司 医药级美法仑及其盐酸一盐、二盐的制备方法
CN102757357A (zh) * 2012-07-25 2012-10-31 平湖优康药物研发中心 一种抗肿瘤药物美法仑的合成工艺
WO2014141294A2 (fr) 2013-03-11 2014-09-18 Biophore India Pharmaceuticals Pvt. Ltd. Procédé perfectionné pour la synthèse de melphalan et de son sel chlorhydrate
US8921596B2 (en) 2010-11-04 2014-12-30 Emcure Pharmaceuticals, Ltd. Process for the preparation of melphalan hydrochloride
CN106083693A (zh) * 2016-06-14 2016-11-09 王健 N‑邻苯二甲酰基对‑(二羟乙基)氨基‑l‑苯丙氨酸乙酯的合成工艺
WO2021092162A1 (fr) * 2019-11-05 2021-05-14 Aditya Kunjapur Biosynthèse de para-nitro-l-phénylalanine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3032584A (en) * 1953-03-17 1962-05-01 Nat Res Dev p-bis-(2-chloroethyl) aminophenylalanine and the process for the production thereof
EP0128684A1 (fr) * 1983-05-25 1984-12-19 Sumitomo Pharmaceuticals Company, Limited Procédé de production de 3-(3,4-dihydroxyphényl)sérine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3032584A (en) * 1953-03-17 1962-05-01 Nat Res Dev p-bis-(2-chloroethyl) aminophenylalanine and the process for the production thereof
EP0128684A1 (fr) * 1983-05-25 1984-12-19 Sumitomo Pharmaceuticals Company, Limited Procédé de production de 3-(3,4-dihydroxyphényl)sérine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 90, no. 25, 18th June 1979, pages 663-664, abstract no. 204445s, Columbus, Ohio, US; T.A. TENG et al.: "Synthesis of enantiomorphic o-methoxy-p-Äbis(2-chloroethyl)aminoÜphenylalanines", & HUA HSUEH HSUEH PAO 1978, 36(3), 233-7 *
JOURNAL OF CHEMICAL SOCIETY, part I, 1954, pages 2409-2417; F. BERGEL et al.: "Cyto-active amino-acid and peptide derivatives. Part I. Substituted phenylalanines" *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0317281A2 (fr) * 1987-11-19 1989-05-24 The Wellcome Foundation Limited Formulations pharmaceutiques contenant du melphalan ou du chlorhydrate de melphalan, le melphalan et le chlorhydrate de melphalan et procédés pour les préparer
EP0317281A3 (en) * 1987-11-19 1989-08-09 The Wellcome Foundation Limited Pharmaceutical formulations containing melphalan or melphalan hydrochloride, as well as melphalan and melphalan hydrochloride and processes for preparing them
EP2268827A1 (fr) * 2008-03-20 2011-01-05 Navinta, llc. Procédé permettant de produire du melphalan optiquement pur
EP2268827A4 (fr) * 2008-03-20 2011-09-07 Navinta Llc Procédé permettant de produire du melphalan optiquement pur
US8575385B2 (en) 2008-03-20 2013-11-05 Navinta Llc Process of making optically pure melphalan
CN102030671A (zh) * 2010-10-26 2011-04-27 浙江凯普化工有限公司 医药级美法仑及其盐酸一盐、二盐的制备方法
US8921596B2 (en) 2010-11-04 2014-12-30 Emcure Pharmaceuticals, Ltd. Process for the preparation of melphalan hydrochloride
CN102757357A (zh) * 2012-07-25 2012-10-31 平湖优康药物研发中心 一种抗肿瘤药物美法仑的合成工艺
CN102757357B (zh) * 2012-07-25 2014-04-23 平湖优康药物研发中心 一种抗肿瘤药物美法仑的合成工艺
WO2014141294A2 (fr) 2013-03-11 2014-09-18 Biophore India Pharmaceuticals Pvt. Ltd. Procédé perfectionné pour la synthèse de melphalan et de son sel chlorhydrate
CN106083693A (zh) * 2016-06-14 2016-11-09 王健 N‑邻苯二甲酰基对‑(二羟乙基)氨基‑l‑苯丙氨酸乙酯的合成工艺
WO2021092162A1 (fr) * 2019-11-05 2021-05-14 Aditya Kunjapur Biosynthèse de para-nitro-l-phénylalanine

Also Published As

Publication number Publication date
JPS62192357A (ja) 1987-08-22
PH23371A (en) 1989-07-14
AU575742B2 (en) 1988-08-04
AU6882887A (en) 1987-08-20
EP0233733A3 (fr) 1988-01-13

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